Integrin CD103 reveals a distinct developmental pathway of autoreactive thymocytes in TCR transgenic mice

Nurcin Liman, Can Li, Megan A. Luckey, Hilary R. Keller, Jie Li, William Hajjar, Jan Wisniewski, Michael Kruhlak, Vanja Lazarevic and Jung-Hyun Park ()
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Nurcin Liman: NIH
Can Li: NIH
Megan A. Luckey: NIH
Hilary R. Keller: NIH
Jie Li: NIH
William Hajjar: NIH
Jan Wisniewski: NIH
Michael Kruhlak: NIH
Vanja Lazarevic: NIH
Jung-Hyun Park: NIH

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Clonal deletion through negative selection is critical to eliminate autoreactive T cells in the thymus. Negative selection, however, is imperfect such that some autoreactive thymocytes can escape thymic deletion and successfully populate peripheral tissues. This is also the case for autoreactive 2D2 TCR transgenic T cells, a widely employed mouse model in studying the pathogenesis of CD4 T cell-mediated experimental autoimmune encephalomyelitis. How autoreactive 2D2 thymocytes evade negative selection, however, remains incompletely understood. Here we show that negative selection of MHC-II-restricted thymocytes, specifically 2D2 TCR transgenic T cells, is associated with the induction of integrin CD103, and that forced expression of CD103 downregulates CXCR4 expression, alters intra-thymic trafficking, and reinforces clonal deletion of immature thymocytes. Stratification of positively versus negatively selected 2D2 T cells based on their distinct coreceptor expression further shows that CD103 does not affect the generation of conventional CD4 T cells but is deleterious for autoreactive CD4, CD8 double-negative 2D2 T cells that correspond to CD69-negative CCR7-intermediate thymocytes, displaying markers of agonistic TCR signalling. Collectively, these results propose CD103 expression as an indicator and contributor of negative selection for MHC-II-restricted T cells, providing further mechanistic insights into the process of T cell selection in the thymus.

Date: 2025
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DOI: 10.1038/s41467-025-61922-8

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